PT96142B - PROCESS FOR THE PREPARATION OF 3-PHENYLGLUTARIMIDE DERIVATIVES ANTAGONISTS OF MUSCLE RECEPTORS - Google Patents

Abstract

PCT No. PCT/EP90/02040 Sec. 371 Date Jun. 11, 1992 Sec. 102(e) Date Jun. 11, 1992 PCT Filed Nov. 28, 1990 PCT Pub. No. WO91/09014 PCT Pub. Date Jun. 27, 1991.Musacarinic receptor antagonists, particularly useful in the treatment of irritable bowel syndrome, of formula (I), or a pharmaceutically acceptable salt thereof, where m is 1 or 2; R1 and R2 are each independently H or C1-C4 alkyl or together represent -(CH2)p- where p is an integer of from 2 to 5; R3 is H or C1-C4 alkyl; wherein Z is a direct link; -CH2-, -CH2O- or -CH2S-; and R4 is a group of formulae (II), (III), (IV) or Het, where R5 and R6 are each independently H, C1-C4 alkyl, C1-C4 alkoxy, -(CH2)nOH, halo, trifluoromethyl, cyano, -(CH2)nNR7R8, -CO(C1-C4 alkyl), -OCO(C1-C4 alkyl), -CH(OH)(C1-C4 alkyl), -C(OH)(C1-C4 alkyl)2, -SO2NH2 , (CH2)nCONR7R8 or -(CH2)nCOO(C1-C4 alkyl); R7 and R8 are each independently H or C1-C4 alkyl; n is 0, 1 or 2; X and X1 are each independently O or CH2; q is 1, 2 or 3; and "Het" is pyridyl, pyrazinyl or thienyl.

Description

PROCESS FOR THE PREPARATION OF 3-FENILSLDT AR IMIDA DERIVATIVES MUSCARINIC RECEPTOR ANTAGONISTS

DESCRIPTIVE MEMORY

Re? juice

The present invention preparation of larroent antagonists useful in the treatment relates to a process for that of muscarinic receptors, part of the irritable bowel syndrome, of CI structure formula)

H or a pharmaceutically acceptable salt thereof, where m is 1 or 2; R 'and R each independently represent H or alkyl or together - <CH. „,,) - where p is an integer from © xem pio, a group of formula:

up to 5; R '"' represents H or C1 -C4 alkyl; 2 represents a CH-alloy, .., -, --CH. ~, O · or -CH ^ SJ and R ^ ^- represents, for

where R © R represents -sm, for example, R, then there is C ·., £ ·., or,!. 4 xyl C. ₍ -C _laughs .

Said process consists, however, of a compound of formula of structure;

ro.

(II) ορθέ R t Fí, R and m are · oefin ies in the same way pu © antsrior go · with a composo of TÕrmulaí | _

-Z-R

ΙΠ.1 where © is a separable group.

χ \ ·

This invention relates to certain 'deK.i.vad © e.xáe 3-phenyl' -Í- ^{S, T} **** '' glutarimide. The compounds of the invention are muscarinic receptor antagonists, which are selective for smooth muscle muscarinic sites rather than cardiac muscarinic sites, and which have no significant antihistamine activity. Thus, the compounds are useful in the treatment of diseases associated with altered motility and / or smooth muscle that can, for example, be found in the intestine, trachea and bladder. These diseases include irritable bowel syndrome, diverticular disease, urinary incontinence, esophageal achalasia and chronic obstructive airway disease.

According to the invention, compounds of formula <1> are provided:

and their pharmaceutically acceptable salts, where m is 1 or 2;

R ¹ and R ² each independently represent H or something CC. or jointly represent - <CH.14 ip where ρ is an integer from 2 to 5;

R '' represents H or alkyl in which 2 represents a direct bond, -CH _O -, -CH. „, O- or

-CH _The SJ and R 'represents a group of structure formula;

Where

9

R and R each independently represent H, C-C »alkyl, C» ”C _Z alkoxy, - <CH _O ) OH, halo, trifluoro 4 14-7Q 2 n-romethyl, cyano, - <CHNR'R '', -COCalkyl C.-C ₄ >, 2 n 14

-0C0 (C'-C1 alkyl), -CH (OH) (C-C2 - alkyl), -CCOH1 Cl2 * 4 »X * {.

kilo C.-CJ, -SO ..., NH._ ,, -ÍCH „) CONR '* R ~ * or> COOCal—

Δ VSV} -) yn kilo C -C) j 7 ft ^1, 4

R and R ~ each independently represent H or C ^-C ^ J alkyl n is 0, 1 or 2

X and X ^ each independently represent 0 or ch. _? ;

q and 1, x or O,

Het represents pyridyl, pyrazinyl or thienyl.

Halo means F, Cl, i3r or I. The alkyl and alkoxy groups of 3 or 4 carbon atoms can be straight or branched. Preferred alkyl and alkoxy groups are methyl, ethyl, methoxy and ethoxy.

R '

R are preferably each H or CH.- ,.

R e, preferentially, me t i1 ê, preferably,

-CH.-, ^-

R4 is preferably a group of structural formula

♦ 5 A where-- R and R are each independently chosen from 1

H, halo, hydroxy and C1 -C4 alkyl and X and X are defined in the same way as before.

Pharmaceutically acceptable salts of compounds of formula (!) Include acid addition salts, such as hydrochloride, hydrobromide, sulphate or bisulfate, phosphate or hydrogen phosphate, acetate, besylate, citrate, funtarate, gluconate, lactate, maleate, mesylate salts , succinate and tartrate. For a broader list of pharmaceutically acceptable salts, see, for example, the -Journal of Pharmaceutical Sciences, Vol. ββ, N2 1, January 1377, pages 1-13. These salts can be prepared conventionally, e.g. by mixing a solution of the acid and the free base in a suitable solvent, e.g. ethanol, and recovering the salt by adding acid either as a precipitate or by evaporating the solution.

Compounds of formula <I can be prepared by the following route;

Compounds (I)

R, R ^, R '~', R, 2 & m are for the structure formula CX) and QB r, Cl, I, a1c to our 2 f on i 2 oxy C -C ^, benzenosau1f on i1oxi, to1uenossu1f on i1 loxy ') or trifluoromethanesulfonyloxy.

defined in the same way as a leaving group, e.g. g. methanossu .1 f on i 1 ox i), oxy Ce.g. p — toluenesulfone The reaction is preferably carried out in the presence of an acid acceptor, such as sodium carbonate or sodium potassium, sodium bicarbonate, triethylamine or pyridine, in a suitable organic solution, eg acetonitrile, at a temperature not higher than reflux. reaction temperatures of 50-120 ° C are generally desirable and it is more convenient to process the reaction under reflux.

In the preferred technique, compounds of formulas of structure (II) and <III) are refluxed together in acetonitrile in the presence of sodium bicarbonate. The product of formula (C1) can be isolated and purified conventionally.

The starting materials of formula CXI) can be obtained by conventional processes, such as those described in the Preparations section below.

r

c onvention.

structure formula (III) used in the Examples is, however, described in the Preparations section below.

A typical route for the 'rfe' compounds ^: 'formula of the CII structure) is as follows;

R ¹ R ³

B ° ~ —C - ^N - Benziio

SOC1 „

R ¹ R ³

Cl - (CHy ^ —C- N-Benzyl

Eh

Eh

R ¹ R ³ /

NC

CH / NaH 'z

CH -

Ç — ’n — Benziio

CN

CE ^ = CH-CN / NaC) Et or NaORr ¹

Hl

NC CN

R ¹ R ³ (° ½¼ - ^N —Benziio - (IV)

R ² Ci) Cyclization, concentrated hydrochloric acid, reflux

Cii) Removal of the benzi1o group

C e. g. HCOOH / MeOH / Pd / C)

Compounds CII)

The compounds of formula of formula (I) can also be prepared by cyclizing the compounds of formula (V):

Cyclization is typically carried out using concentrated mineral acid, preferably concentrated hydrochloric acid, typically under reflux.

The starting materials <V5 can be prepared in a manner analogous to the method previously described for the preparation of the N-benzyl i nter meds (<ί V).

Some of the compounds of formula (I) in which R ⁴ is a substituted phenyl group can be converted to other compounds of formula (structure CI) as follows:

<s> Ur »-CCU substituent / something in the phenyl group can be selectively reduced to -CH .-. OH. Cf hi ♦ C.

aluminum and lithium dreto is the most suitable reducing agent. The reaction is typically carried out in a suitable organic solvent, e.g. ether, between 0 ° C and room temperature. It is generally more appropriate to use the starting material in the form of its methyl ester.

(b) A hydroxy substituent on the C-to -OCO (C1 -C alkyl) J. A of the alkanoyl chloride or bromide phenyl by acylation. —C ,, or one can be used anhydride

The presence of an acid acceptor is possible. The picamenf reaction carried out at room temperature in a suitable organ, e.g. doxane.

"Ί 0 pref eé t i? 1 vente

-CO (at 1 ch i 1 o C. -C, ') in the group f e1 A (c) A nile substituent can be reduced to a formula substituent

-CHCOHXalkyl Sodium borohydride is a suitable reducing agent. The reaction is typically carried out between 0 ° C and room temperature in a suitable organic solvent, e.g. methanol.

(d) A substituent -CCH_) COO- (C-C) alkyl, preferably when the alkyl group is methyl, can be converted to VUNR R by reaction with ammonia or the amino acid of the 7-pi '' ”7 appropriate R'R'iMH. When R '' and R '' are both H, it is generally more convenient to use aqueous ammonia (0.880), although the reaction can be carried out using ammonia in a pure organic solvent in a pump.

such as methanol or ethanol, or ammonium The reaction with methylamine is most conveniently carried out in ethanol. Although in some cases the reaction can proceed at a satisfactory rate at room temperature, it is generally necessary to heat up to 120 ° C, preferably from SO to 100 ° C. For volatile amines, the reaction is best carried out in a pump.

appropriate R R NH. THE

Ce) A hydroxymethyl or hydroxyethyl substituent on the phenyl group can be converted to -CH.-.NR '' R '' or - (CH .-.,) ..., NR ^/ R * ”'first by reaction with chloride fio.it.

nile and secondly by reaction with ammonia or the amine reaction with thionyl chloride is typically carried out with heating, preferably under reflux, in a solvent such as methylene chloride. THE

A reaction with cable ammonia in a solvent, under reflux, can such as ethanol, and a heating, e.g. being necessary.

(f) A -C0 substituent (CC-C ^ alkyl) can be converted to -C (OH) C-C calkyl by reaction with a

J. A (Cj — C ^) a1-i-1-thio or brome, chloride or iodide of CC -C-l-alkali-magnesium (eg methyl lithium, methylmagnesium bromide, sodium, methyl magnesium iodide or chloride meth 1 magnesium .. The reaction is typically carried out in a solvent, such as · ether, at a temperature ranging from 0 * C- to room temperature.

<g) An iodine substituent · can be converted to CC ^ - -C ^alcoxycarbonyl by reaction, typically at room temperature, with carbon monoxide in an alkane! C ^ -C ^ which contains a Ce.g. Potassium carbonate! and a palladium (II) Ce.g. bis (tri-phenyl. 1 phosphine) palladium chloride <11) 3.

The selectivity of the compounds as Riuscarinic receptor antagonists can be measured as follows.

Proquinhos are sacrificed and the ileum, trachea, bladder and right auricle are removed and suspended in a physiological saline solution under a tension of resting at 1 to 32 ° C ventilated with 0 ..., 95% and C0. _, 5%. Contractions of the ileum, bladder and trachea are recorded using an isotonic (ileum) or isometric (bladder and trachea) transducer. The frequency of spontaneous right atrium contraction is derived from isometrically recorded contractions.

τ

The dose response curves for either acetylcholine (ileum) or carbacol (trachea, bladder and right auricle) are determined using a 1-5 minute contact time for each agonist dose, until reaching the maximum response. The organ bath is removed and the container is refilled with physiological saline solution, which contains the lowest dose of the test compound. The test compound is left to equilibrate with the tissue for 20 minutes, and the agonist dose response curve is repeated until the maximum response is obtained. Remove the organ bath and refill the container with physiological saline containing the second concentration · of the test compound and repeat the previous process. Typically, four concentrations of the test compound in each tissue are evaluated.

The test ccrniRoste concentration that causes the agonist concentration to double to determine the initial response Γvalue pA ... is determined - Arunlakshana and Schild (1959),

Brit. J. Rharmcol. , yeah. 4B-5B3. Using the above analytical techniques, tissue selectivity for antagonists of the Biuscarinic receptor is determined.

The activity against the · agonist induces bronchoconstriction or contractility in the intestine or bladder in response to changes in heart rate, and is determined in the anesthetized dog.

A to c χ. the oral route is doubled. at the·

- - »y--.

tI Γ bt!

conscious by determining the effects of the compound, for example, on heart rate, pupil diameter and intestinal motility.

The affinity of the compound for other cholinergic sites is determined in the rat, after administration, either intraperitoneally. In this way, it is determined the doubling of the size of the pupil well covered by the dose of salivation and the trembling of oxotremorine by intravenous either

OO'5G? CHUSõl -Sí that inhibits res50%.

For administration to man in the curative or prophylactic treatment of diseases associated with altered motility and / or smooth muscle tonons, such as irritable bowel syndrome, diverticular disease, urinary incontinence, esophageal achalasia and chronic obstructive airway disease, oral dosages of the compounds will range from 3.5 to 350 mg per day for an average adult patient <70 kg). Therefore, for a typical adult patient, individual tablets or capsules will typically contain from i to 250 mg of active compound, in a suitable pharmaceutically acceptable carrier or carrier for administration alone or in multiple doses, once or several times a day.

Dosages for intravenous administration will typically be in the range of 0.35 to 35 mg po? ' single dose, as required.

In practice, the doctor will determine the current dosage which will be best suited for an individual patient and it will vary, with the patient's age, weight and response in particular. The above dosages are exemplary of the case * medium, but there will certainly be individual situations in which higher or lower dosage ranges are deserved and these are within the spirit and scope of the present invention.

For use by man, compounds of formula (I) may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier chosen in view of the intended route of administration and standard pharmaceutical practice. Powder?' example, can they get together? ' administered orally in the form of tablets, which contain excipients such as starch or lactose, or in capsules or eggs, whether alone? ' mixed with excipients, or in the form of elixirs

or suspensions, which contain flavoring and coloring agents. The compounds can be injected relatively, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of formula <11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases associated with impaired motility and / or smooth muscle tone, such as the syndrome. irritable bowel, diverticular disease, urinary incontinence, esophageal achalasia and chronic obstructive airway disease.

The event also includes a method of treating a human being to cure or prevent a disease associated with altered motility and / or smooth muscle tonus, such as irritable bowel syndrome, which comprises the treatment of that being human with an effective amount of a compound of formula (I>), or a pharmaceutically specific salt or composition thereof.

The invention also includes the new intermediates of formula III).

The following Examples, where all temperatures are in ° C ', illustrate the invention:

Example 1

Preparation of <8, S ') - 3-C3-C {\ i-4-hydroxyphenethyl-N-methylamino) -3-mst i1bu t-1 — iI3-3-phen i1g1u tar i mi da

A mixture containing CR,) -3- (3-methyl 1-3-methyl 1 amobutyl-1> ~ 3-phenylglutamide <0.58 g - see Preparation il), 4-hydroxyphenethyl bromide, 41 g), sodium bicarbonate <2 g) and acetonitrile (20 ml) was heated under reflux for 20 hours. The mixture was partitioned between dichloromethane (CSO ml) and water (CSO ml), the layers were separated and the aqueous layer was further extracted with dichloromethane (C2 x 50 ml). The combined dichloromethane extracts were dried (CMgSO4) and concentrated in vacuo to give a foam which was purified by chromatography on

6 ’

column on silica eluting with dichloromethane containing 10% methanol up to 5%>. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam.

Yield: 0.26 g.

An «tl ise%»

Found;

C-70.33 ‘, H-7, '35‘, N ~ 6.30

Ca1c u1ado for C__H_-N-O 4, ♦ -? · * .. · jE .tL. 1 / 2EtOH, 1 / 2H .-. 0: C-70.37; H-3.2 3; N £ * · - «£ - ' R. M. Ν .- * Η CCDC1 ^:> £ = e , 30-7,80 C br s, IH); 7.45 · C m, 5H>; 7.10-7.00 Cd, 2H); 6, SS — 6.75 C d, 2H) ι 2.80 ' C m, SH), ' 2.45-2, 10 C m, 3H> 2.30 C s, 3H), ' »Ttw J 10-1.85

2H>; 1.60-1.40 Cform, 1H. ‘>; 1.3-5-1.20 Cm, 1H? J 1, OO Cs, 6H>

ppm.

Example

Preparation of (R, S) -3-C3- (M-4-chlorophenethyl-N-methylamino) -3-methyl but-1-3- 3-phenylglutarimide

A mixture that contains (R, S) -3- (. 3-me ti 1 -3-me ti 1 am i nóbut-li 1) -3-pheniIglutarimide <0, .58 g - see Preparation 11), 4-chlorophenethyl bromide (0.47 g), sodium bicarbonate (2 g) and acetonitrile (20 ml) was heated under reflux for 17 hours. The mixture was partitioned between dichloromethane (£ 0 ml) and water (50 ml), the layers were separated and the aqueous layer was further extracted with dichloromethane (2 x 50 ml). The combined dichloromethane extracts were dried (MqSO.,) And concentrated in vacuo to give an oil that was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% to 47 ° C). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil which crystallized from ethanol.

Yield! 0.03 g mp 135-133 ° C.

Annáiss%;

Found;

Calculated for C _oc. H _o1 C1N ..., O .. _; ,!

C-70.44; H-7.53; N-5.52 C-70.32; H - 7.32; N-5.56

R.M.N. ~ ¹ H ICCD1 £ · = 7, .35-7, .3 5 br (1H); 7.45 magnet, 3H); 2 , 75—2.15 magnet, 8H>; 2.20 (s, 3H) 1 2.05- -1.35 (H); 1.90- 1.85 µm, (H), * 1.45-1.35 magnet, ÍH), ’1.30- -1.20 1H); 0.35 (s, 5H) ppm.

í m, il »j

Example 3

Preparation of IR, 5:) - 3-C3-ÍN-4-methyl.1 phenethyl-3-methyl-1-bu-1-i I Zi -3-phenyl 1 u tarimide

H

One mixture contained

<R, 8) -3- <3-roeti 1-3-roethylaminobut — 1-i 1) -3-phenylglutarimide CO, SS g - see Preparation 1.1), 4-methylphenethyl bromide <0.40 g), pecking sodium bonate <2 g) and acetonitrile <20 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (50 ml) and water (50 ml), the layers were separated and the aqueous layer was further extracted with dichloromethane (2 x 50 ml). The combined dichloromethane extracts were dried (MgSO _rf ) and concentrated in vacuo to give an oil that was purified by column chromatography on silica eluting with dichloromethane containing <1% methanol up to 5%). The fractions containing the product were combined and concentrated in vacuo to give the title compound as a colorless oil which crystallized from ethanol.

Yield; 0.3 g

mp 145-148 ° C.

%% Analysis Found;

Calculated for

C-76.81; C-75.81;

H-8.51; N-5.83 H ™ 8/43 J N — 5.83

R.M .N.- ~ H <CDC1._,) £ = 7.35-7.8 5 (brs, H); 7.40-7.2 · <ro, SH); 7, 10 <ε, 4H) i 2.75-2.20 (ro, 8H); 2.35 <s, 3H) 2> 25 <s, 3H); 2.10-2.00 <m, H); 1 , 35-1.85 (m, IH); 1.5 1.40 <ro, 1H); j ί, 30-1.20 <m, 1H); 0 , 35 <s, 3H); 0.30 <s 3H) ppm

Example 4

Preparation of <R, S) —3— £ 3— <H — phenethi 1 —N — meti1ami no) -3 — me tilbut-l-ã 13-3-pheniIglutarimide

A mixture containing CR, S) ”3 ~ <3 ~ methyl-3 - mefilamino but-1-i1) -3-phenylglutarimide <0.58 g - see Preparation 11), phenethyl bromide <0.38 g ), sodium bicarbonate (1.0 g) and nitrile acetate (20 ml) was heated under reflux for 5 hours, water was added and the mixture extracted with dichloromethane (SO ml). The combined dichloromethane extracts (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol <10% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colorless solid.

It was <2 x dry

Yield! 0.14 g mp 135-137 ° C

Anã1ise% »

Found:

Calculated for already £? £>. £. . £. „£.

C-75.7S; H-8.17; N-6.99 C-76, 49 i H — 8.22; N-7.14

R.M.N.- HCDCD1.-,) £

S, 20-8, 0 © í fo r í

(H). · Afj1S

fí! , i oh); 2.80-2.2 © e ^m? SH); 2125 is, SH); 2.10-2.0 © magnet, H); 1.95- -1.85 magnet, ÍH) ί 1.5 © - 1.4 μm, H); i, 35-1.2 © í m, 1H); 1, ©________________ is, SH); ©, 95 ís, SH) ppm.

Example 5

F 'repa r to c & o ir,

CS-Í Ν-4-chlorophenethyl-N-methylamino) prop ~ i13-3-phenylglutarimide

a mixing file that has a format of

to see

CR, 3) -3- <3-methylaminoprop-1-I) -3-phenylGlutarimide <0.5 g Preparation 4;

·), 4-chlorophenethyl bromide <0.42 g), sodium bicarbonate <1.0 g) and acetonitrile <20 ml) was heated under reflux for 8 hours and then was partitioned between dichloromethane C So κι I) and CSO ml water). The layers were separated and the aqueous layer was further extracted with dichloromethane (3 x 50 ml). The combined dichloromethane extracts were dried (MgSCr) and conZ |.

centered in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane which contained methanol (0% to -8%). The fractions containing the product were combined and concentrated in vacuo to give a foam which was later purified by column chromatography on silica eluting with chloroform which contained methanol <0% to 8%). The product-containing fractions * were combined and concentrated in vacuo to give the title compound as a colorless foam.

Yield; 0.06 g.

Ana 11 if? £; Found;

Calculated for C .. ,,., H ^, C 1 N _o 0 ..,. Z2H ... 0;

. & · * · .. * Am. / Am. .Am, 1m

1,

C-68.17; H-6.76J N ~ 6.74

C — 67.71: H ™ 6.32 ‘, N — 5.87

R.M.N.- H (CDCl, - *) S = 8.00-7.35 irs, (1H); 7.40-7.25 (d, 2H); 2.75-2.20 (m, 10H); 2.25 <s,

2H); 1.60-1.30 Cm, 2H) <m, 7H): 7.15-7, 0

3H); 2.05-1.80 C m, ppm.

Example β

Preparation of nolprop-l-i, 1 3 '

3 ~ - (Ν-4-methyl 1-pheneth 1 -N-methyl 1 ami 3-phen 1 g 1 u ta r i m i da

A mi st-u ra that - i 1) -3-phen i 1 g. 20 m.1) heated heated fox, was partitioned between The layers were separated with dichloromethane <3 x 50 c line <R, · 3) -3- (3-met i .1 am i nop r op-1 5 g - see Preparation 4>, sodium icarbonate bromide <1.0 g) and acetonisob reflux for 8 hours (in loromethane series <50 rol) and water <50 ml), and the aqueous layer was further extracted (ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam that was purified by column chromatography on silica eluting with dichloromethane containing <0% to 6% methanol). The fractions containing the product were combined and

concentrated in vacuo to give a foam that was later purified by column chromatography on silica eluting with chloroform containing CO% methanol up to 3%). The product-containing fractions were combined and concentrated in vacuo to give the title compound in. form of an i ncolor foam.

Makes 10 to 09 g.

mnètlise% <

Found;

Calculated for

C._, Μ. n. H „0. 1 / 4CHC1i .ώ4 ·. ©, ώ Ζ Ζ ·.

C-70.55; H-7.47! N-5., 3 1

C-70.95; H-7.92; N-S, 33

R.M.N.-H CCDCÍ ..,) 8 = 7.95-7.35 Cbrs, IH); 7.45-7.25

Cm, 5H); 7.15-7.05 CAbq, 4H>; 2.75-2.50 Cm, SH); 2.50.20 Cm, 4H>; 2.35 Cs, 3H); 2.25 Cs, 3H); 2.10-1.35 Cm,

2H); 1.75-1.35 Cm, 3H) ppm.

ϊ

Preparation of <R, S) -3- £ 3- £ N- £ 2- <i ndan-5- i 1) et · ϊ .1 3 -N-methylaminoprop-1-i13-3-phenylglutarimide

A nude that contained i13-3-phenylglutarimide <0.5 g - vsr Preparation 4),

-bromoet i13 x ndano <0.43 g see Prsparaç

123 sodium bicarbonate (1.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours then it was partitioned between dichloromethane <50 ml 3 and aqueous water. ). The layers were separated and the aqueous purple layer was still extracted with dichloromethane <3 x 50 ml 3.

and concentrates in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing combined dichloromethane were dried <MgS0.3 A · m & tanol <0% to 8%). The fractions containing the product were

· 'Ί ο * combined and concentrated in vacuo to the very last foam that was later purified by column chromatography on silica eluting with chloroform containing <0% to 5% methanol>. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a 2-fold foam.

Yield! 0.09 g.

Ané. 1 i if%; t n c o n t r a d ua1cu1 for Ο .-, ^ Η .-, .-, Ν .-, Ο ..,. 1 / 2H.-.0;

0-75.07; H-7.82; N-S, 87

0-75.51; H-7.80; N-S, 77

what ..

^; H-NMR (CDC1 '> £

8.05-7.95 (ib, ÍH);

7.20 <m, · SH); 7.20- 7.1 5 íd, 1.H) ; 7.05 <s, 3. H) / 6 to 95 * <d, 1H>; 21 ‘35 —2.85 <t, 4H>; .42 f 75-2.70 í. m, or \ » AVI 1? í · “> You? ç, ζ ίϊϊ t 2H> 2.50-2.30 <i>! , 4H); ~ · ~ T 30-2.20 <m, 2H); 2.30 3H); * 7 · * .U. f 15—1.85 <m, 4H> , 1 , 5Q- .1 , 35 µm, 2H) ppm.

Preparation of <PS) ~ -3 ~ ’3 - <N-phenyl 1-N-methylamine

-i-i 13-3-pheni iglutarimide ~ p

A mixture containing <R, 3) -3- <3-methylaminoprop-1— i1) ~ 3 "phenylglutarimide <0.5 g - see Preparation 4), phenethyl bromide <0.35g), sodium bicarbonate (. 1.0 g) and acetonitrile <20 ml) was heated under reflux for S hours and then the mixture was partitioned between dichloromethane <50 ml) and water <30 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (3 x 30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing, methanol <0% to

%)

The fractions containing the product were combined * ι; λ concentrated in vacuo to give the

title • ~ »p na 1 * ΟΓΙΒ8 of a foam.

Yield! O, 09 g.

% I Analysis

Found; C-73.95; H-7, -65; N-7, . ^c .q Calculated for C „-H. .N .Cf. . 1 / 2H _0: C-73.96; H-7, 551 N-7, 50 Ε.Μ, Ν .- ^ Η <CDC 1 .., 3 S = 8 , 05-7.95 (brs, 1H3) 7.45-7 , i 0 <m, 2H 3; 2.80-2.70 <m, · 2H 3; 2.70-2.50 <m, 3H 3, * 2.50-2 ι 30 <m, 4H); 2.30-2.20 <m, HH3; 2.25 <s, 3H3 i 2.10- ί, 85 <m, 2H3; 1.60-3.30 <m, 2H3 ppm.

<R, 8 3 -3- Γ P r epa rtion. 3- <N-benz i 1 -N-me til am i no 3 -p r op-1-ί13-3-f en i 3 g1u ta r i m i da

A single use of <R, 8 3 -6- <N ~ benzyl 1 -N-met i 3 am i no 3 -1, 3-di-cyano-3-phenyl-hexane <19.0 g - see Preparation 33 in concentrated hydrochloric acid <3.00 ml 3 was heated under reflux for 2 hours. Water <500 ml 3 was added carefully and the mixture was neutralized <pH = 83 by addition of sodium bicarbonate. The mixture was extracted with dichloromethane <3 x 150 ml 3, the extracts were formed and then dried <Ng8O ^ 3 and

concentrated in vacuo to give the title compound as a gum.

Yield 15.0 g.

Ρ.Μ.Ν .- ^ Η <CDC1. ^) £ = S, 30-8, · 20 <brs, (H) 7.45-7.20 <m, 10H); 3.4-5 <s, 2H) J 2 , 65-2.55 <m, l.H)  2i50—2.25 (m, 4H); 2.1-5 (s, 3H); 2.10-1 , 85 (m, 3H); 1 , 65-1.40 (m, 2H) ppm.

Example 10 β

Preparation of <R, 8) -3-Γ-3- (N-benzyl-N-methylamino) ·

111but1-113-3-f en11g1u ta r i m i from “Γίϊθ ·

Ph Me

A solution of <R, 8) -6 ”<N-benzyl“ N-methylamino) -i, 3-dicyano-6-methyl-3-phenyl-heptane <14.0 g - see Preparation 101 in concentrated hydrochloric acid < 70 ml) was heated to reflux The mixture was diluted with water <100 ml) and was added by the addition of sodium bicarbonate. The mixture was basified for 2 hours <pH = ture was extracted with dichloromethane <3 x ISO ml) and the extracts were combined and then dried (MgSO4) and concentrated in vacuo to give the title compound as of a brown oil that crystallized after standing.

Yield; 11 g.

A sample recrystallized from ethanol had mp 104-106 ° C.

«Ί τ

Aná1χ se% ί Found:

Calculated for Οΐ -., ^ Η .-, ^ Ν .- ^ Ο ..., ί

C-7G, 4 &;B-7.30; N-7.24 C — 76, 15 J H — 7.33 N — 7.40

¹ H NMR CCDCI .. *) 8 = 7.30 · Cm, 10H); 3.45 Cs, 2H); 2.65-2 1.65-1.50 Cm, 2H); 1.45-1.30 Cm

7.80 Cbrs, ÍH)! 7.40-7.20

Cm, 5H); 2.00 Cs, 3H);

1Η) ί 1.05 C s, 6H) ί ppm.

The following preparations illustrate the preparation of;

new starting materials in the previous Examples!

Preparation_1

Preparation of 3-CN-benzyl 1-N-methylamino) -l-chloropropanc hydrochloride

See also J. Chem. Soc., Cl344), 2633

S0G1.

CHC1,

Cl .HCl

Thionyl chloride (22 ml) was added dropwise to a cooled solution (0 ° C) of 3-CN-benzyl-N-methylamino) -propan -I-ol <32.8 g) in chloroform C 100 ml) . The mixture was allowed to warm to room temperature and then was heated under reflux for 1 hour. The mixture was concentrated in vacuo to give an oil which was triturated with ethyl acetate to give the title compound as a colorless powder.

Yield: 32 g.

NMR- ^I H CCDCI,. /! 8 = 7.70-7.60 Cm, 2H) J 7.50-7.40 Cm,

3H) ί 4.35-4.15 C m, 2H); 3.75-3.60 C m, 2H) J 3.35-3.25 c m,

<'•' 3H); 3.15—3.00 Cm, 1H); 2.55 Cd, 3H); 2.60 - 2.50 Cm, 1H);

2.45-2.30 Cm, 1 H) ppm.

Preparation 2 Preparation of C R, 3) -4-C N-benzyl-N-roethylamino) -1-cino-1-phenylbutane

Ph

CN + C

Sodium hydride · C4.5 g of a 6-0% dispersion in mineral oil) was added in portions to a solution of phenylacetonitrile · Cl 1.7 g) in anhydrous tetrahydrofuran · C100 ml). When the addition was complete, the mixture was heated under reflux for 20 minutes and was then allowed to cool to room temperature. 3- C N-Benz i 1 -N-meti 1 am i no) -1 - c 1 or dp r opane, hydr oc 1 or to see Preparation í) was ground · with sodium hydroxide pellets · to give an oil that was dissolved in anhydrous tetrahydrofuran (<100 ml) and added dropwise to the phenylacetonitrile solution. The mixture was heated under reflux for 1.5 hours. The tetrahydrofuran was evaporated in vacuo and the residue was partitioned between dichloromethane (200 ml) and water (100 rolls). The mixture was adjusted to pH = 7 by adding · · solid carbon dioxide, tofôib layers separated and aqueous layer was sa ^ ^j ractada exx-UTRA once with dichloromethane <1:00 roll 2 x). The combined dichloromethane extracts were dried (CMgSO ^,) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing C0% methanol to 1 · ϊ »ft 'X

The fractions containing the product were combined and

1 »concentrated in vacuo to an oil.

mentioned sm give the compound

Yield; 15.4 g.

Κ.Μ.Ν .- ^ Η CCDC1 ._, 3 £ = 7.50-7.25 • J

Ct, IH) ί 3.50 Cs, 2H) J 2.50-2.40 (t 2.05-1.90 Cm, 2H3; 1.75-1.55 Cm, 2H3 title ·

Cm, 10H): 3.35-3.75

2H)! 2.20 C s, 3H 3;

ppm.

Preparation 3

Preparation of CR, S3-5-CN-benzyl 1-N — methylamino.3-1, 3-di— cyano-3-phenyl-hexane

ch ₂ <^ ^x CN

NaOPr ¹ dioxane

Sodium hydride <0.2 g of a 60% dispersion in mineral oil) was added to a solution of 4-CN-benzyl-N-methylamino) -l-cyano-1-phenylbutane <15.0 g - see Preparation 23 and acrylonitrile <4.0 ml 3 in 1,4-dioxane. The mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. Water C100 ml 3 was added and the mixture was neutralized 7) by the addition of solid carbon dioxide and then

C pH was extracted with dichloromethane <3 χ 50 ml), dichloromethane with vacuum to give the title compound

Yield; 13 g.

The extracts. were dried (CMgSO ^) and concentrated in the form of a

Κ'.Μ.Ν .- ^ Η CCDCl ^.) 8 2Η); 2.65-2.20 ί m, 5Η);

1.75-1.60 Cm, 1H); 1.40-1

- - * · ν Α. . : 'ί *' ^{Λ 5} ^

7.50-7.25 Cm, 10Η>; 3.45 Cs,, 20-2.00 Cm, 3H); 2.10 Cs, 3H);

(M, 1H) pp.

Preparation ........ 4

CR Freparation, 8) —3— (3 methylaminopropyl) 3 — phenyl glutarimide, format

H

Has 10% palladium on carbon CS g been added in portions? to a cooled solution C0 ^ff C) of CR, S) ~ 3-C3-CN ~ benzyl-N-roethylamino) propyl -1 3-3-phenylglutarimide (15.0 g - see Example 9) in methanol < 100 ml) and formic acid C15 ml). The mixture was allowed to warm up to room temperature and stirred for 1

hours and then the title compound was filtered and concentrated in vacuo to give

Rend i roertto; 15 g.

R.M.N.- H CCDC1.-,) 8 = 3.60-9.20 Cbrs, H): g. 5 <ç _r -8.20 Cs, 2H); 7.40-7.15 Cm, 5H); 3.00-2, 85 Cm, 2H); 2.65 í. £ ·> j 3H); 2.65-2.45 CIH); 2.40—2.20 C m, 3H> 5 2, 10- -1.75 (. m t

3H), ’

1.70—1.50 Cbrs, HI) ppm.

χPreparation 5

Preparation of

-met i 1 -met i I am notoutanoa to os et.il ·

See also -J. Org. Chem., 32, 1322, (1363) 3

Me

CO ₂ Et

MeNH „

Me

EtOH

Me -Me Me-ISr ^^

CO ₂ Et

A mixture containing ethyl 3,3-dimethylacrylate <100 mg) and methylamine (140 ml of a 33% solution in ethanol) in ethanol (400 ml) was left to stand at room temperature for 2 weeks. The mixture was concentrated in vacuo to give an oil which was subjected to fractional distillation in vacuo to give the title compound as a colorless, mobile oil.

Yield, 35.0 g, e.g. 68-75 ° C / 20 mm.Hg.

RM, n- ^A H CCDC1D '= 4.1 (q, 2H); 2.40 (s, 2H); 2.30 is, 3.40), 1.60 is, 1H), 1.25 is, 3H), 1.15 is, 6H> ppm.

I

Preparation β

Preparation of ethyl 3-CN-benzyl-N-methylamino) -3-methylbutanoate

M,

Me

CÓ ^ Et + PhCH Br

Me-N

I

H

K ₂ co ₃

Me

Me-N

Kit><> ^C0 2 ^Et

CH ₃ CN

-Ϊ

Ph

A mixture containing ethyl 3-methyl-3-methylaminobutanoate (95 g - see Preparation 5), benzyl bromide <72 ml3, anhydrous potassium carbonate <138 g3 and acetonitrile (SOC? Ml 3 was heated under reflux for 1.5 hours The mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (SOO ml 3 and 10% aqueous potassium carbonate <800 ml). The layers were separated and the aqueous layer was extracted with dichloromethane <2 x 100 ml 3. The combined dichloromethane extracts were dried ('gS0 ₄ ) and concentrated in vacuo to give the title compound as a colorless, mobile oil.

Yield; ISO g.

.Ρ.Μ.Ν.- ³ · Η (CDC1.-7 S = 7.40-7.20 (m, 5H3; 4.20 iq, 2H3j

3.60 (s, 2H3 '2.55 (s, 2H3, ’2.15 (s, 3H3; 1.35 <s, 6H3!

1.30 (t, 3H 3 ppm.

• / .¾

Preparation 7

Preparation of

-ol

(M-beng ϊ 1 -N-mef i 1 am i no) -3-met á 1 bu tan-1 - ·

Me

A solution of ethyl 3- <N-benzyl-M-methylaminol-3-methylbutanoate (23.6 g - see Preparation 6) in anhydrous tetrahydro-furan (100 ml) was added dropwise over 20 minutes ,

(.'ί;. · Λ euiçppifwSft sei fj »da. of aluminum hydride and lithium <7.2 g) in

-hicJrofuranó anhydrous (300 ml). When the addition was complete, the mixture was stirred at room temperature for 3 hours. Water (<7 ml) was carefully added dropwise followed by ri® ί, 15% aqueous sodium oxide <7 ml) and finally more water (20 ml). The resulting precipitated solid was filtered off and washed with ethyl acetate (3>; 50 ml). The filtrate and washings were combined and concentrated in vacuo to give the title compound as a colorless, mobile oil.

Yield to ί 19.0 g.

• Ϊ

F ?. Μ. N. ~ ^Λ Η (CDC1) δ = 7.40-7, 20 (m, 5H>; 6/15 íBB; 1H) Í 3.95 <t, 2H); 3.65 (s, 2.H); 2.15 c s t * - · Η} í 1 / yo c Ι · t 2H) í 1.25 (s, 6H) ppm.

Preparation 8

Preparation of 2- <N-benzyl 1-N-methylamino? -4-chloro-2-methyl Ibutane, · hi droc 3.oride

Me., Me

Ph

OH soci ₂ ->

Me

CHC1 ₃

Me Me

Me

HCl

A solution of 3- (N-benzyl 1-N-methylamino) -3-methyl Ibu-an-il CS, 9 g - see Preparation 7) in chloroform (20 ml) was added dropwise , for 30 minutes, to a solution of thionyl chloride <4.9 ml) in chloroform (20 ml) at 0 ° C. When the addition was complete, the mixture was stirred at room temperature for 13 hours. Ethanol (-5 ml) was added and the mixture was concentrated in vacuo »to give an oil» which was crystallized from »ethyl acetate» to give the »title compound as a colorless powder.

Yield"; 2.62: bp 164-166 ° C.

Ρ.Μ.Ν .- ^ (CDCl ^) £ = 7.76 Cm, 2H); 7.50-7.40 Cm, 3H);

4.70 (dd, 1H); 3.80-3.65 Cm, 3H); 2.60-2.45 Cm, 5H); 1.70 (d, 6H) ppm.

Preparation 9

Preparation of <R

4- <N-benz i 1 -N-me t i 1 am i no) -1 ~ - c i ano-4-roeti 1-1 — feni Ipentano

Me

Ph

CN + CL

Read me ^ Ph

I

Me

NaH

THF

Me

CN

Me n

Me 'Ph

Sodium hydride <4.4 g of a 50% dispersion in mineral oil) was added portionwise to a solution of acetonitrile <11.7 g) in anhydrous tetrahydrofuran and the mixture was heated under reflux * for 15 minutes. ft the resulting yellow suspension was cooled to room temperature after which 2 — iN — benzyl (N-methylamino) -4-chlorο-2-methylbutane <20 g - freshly prepared from its hydrochloride salt by partition · between dichloromethane and 15% aqueous sodium hydroxide - see Preparation 8) was added and the mixture was heated under reflux for 0.5 hours. The tetrahydrofuran was evaporated in vacuo and the residue was partitioned between dichloromethane (<200 ml) and water <100 ml). The layers were separated and the aqueous layer was neutralized (pH = 7) by adding solid carbon dioxide. The aqueous solution was extracted with dichloromethane <2 x 100 ml), the dichloromethane extracts were combined and then concentrated in vacuo to give a waxy solid that was purified. <MgS0 „) and dried by chromatography. column on silica eluting · with toluene which is up to 40% et © rdieti). The fractions containing the product were combined and concentrated in vacuo to give the title compound · as an oil · orange

Yield; 1 z, .1 g.

Λ <r>

NMR- ¹ } -! CCDCl _q ) $ C (2H / 2H)! 3 ₁ 50 <s ι 1Η);

1.7.5-1.60 Cm, 2H) j 1.10

.... x? ? o \ = 7.50—7.20 CW'i -> 10 $!>! 3.85

2.20-2.05 Cm, 2H); 2.05 Cs,

Cs, 6H) ppm.

3H>;

Preparation 10

CR preparation, 8) -6- (N-benzyl-N-methylamino) -! , 3-dlc iano-6-raet.i 1-3-pheni 1-heptane

Me _x

Me

Me 'Ph CH ^^ CN

CN

Me

Ph

NC

CN Me .X, .Me

N ^X 'Ph

NaOEt Doxan

Sodium C0.46 g) was dissolved in ethanol (CIO ml) and the resulting solution was added dropwise to a solution of 4- C N-foenzi 1 -N-met.i 1 amine) -1 ™ cyano- 4-methyl 1 -1 -phenyl 1-year C17.5 g - see Preparation 9) and acrylonitrile (3.18 ml) in 1,4-dioxane (C30 ml). The mixture was heated to 55 ° C and then allowed to cool. An additional amount of acrylonitrile (4 ml) was added and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between dichloromethane (CISO ml) and water (100 ml) and then CpH was neutralized with the addition of solid carbon dioxide, and the aqueous layer was extracted again with dichloromethane (2 x 10 ml). The combined dichloromethane extracts were dried (CMgSO4) and concentrated in vacuo to give an oil that was purified by column chromatography on silica eluting with dichloromethane containing CO% methanol to 10%>. The product containing fractions were combined and concentrated in vacuo to give an oil that was purified by column chromatography

/) pe1a The layers have been separated

under re ections I i c eluting with 1 less than <15%). The fc ces that contained the * .X 'c on had an effect and the product was combined and concentrated in vacuo to give the title compound as a gum.

Yield; 14 g.

R. M. N. - - H <COC1.-,) S = 7.45-7.15 <m, OH) í 3.50-3.35 <Abq, 2H); 2.50-2.05 <m, 4H); 2.00 <s, 3H); 1.70- ί, 60 <m, 2H); 1.30- · 1.20 Cm, 2H), * .1.10 (s, 3H); 1.00 Cs, 3H) ppm.

Preparation 11

P r epa r tion of <R, · S) <3-me taminaminut-1- i 1) -3-phenylglutamide

10% palladium on carbon <5 g) was added in portions to a cooled solution <0 ° C) of <R, S) -3 ”C3“ <µM ”benzi.lN-methylamino) -3-methyl-butyl -i11-3-pheniIglutarimide <10.5 g - see Example 10) in methanol <100 ml) containing formic acid <11 ml), The mixture was allowed to warm to room temperature and stirred for IS hours and then it was filtered and concentrated in vacuo to give the title compound as a gum.

Yield; 7.1 g.

».

NMR -Λη CCDCl ..,) £ = 7.45-7, (1H); 2 _r 50-2.20 Cm, SH); 2.30 C s, 1.35-1.85 Cm, 1H); 1.55-1.45Cm, 1.10is, 3H); 1.05 Cs, 3H) ppm.

·>? ; C λ

5 C m, 5H); * .. · * · - · ', ·· ¹ J—, {p · » SH); 2, ΙΟ- -1 , · 95 ° C, 1H); 1H); Ι, 35- -1 , 25 Cm, 1H);

Preparation 12

Preparation of 5-C2-bromoefi1) indane

HO

Phosphorus tribromide CCS, 5 ml) was added dropwise to a solution of S-Chidroxieti I) (<14.0 g) CFR-A - -2 139 528) in carbon tetrachloride (C100 ml). The mixture was stirred at room temperature for 0.5 hours and then heated under reflux for 2 hours. Ice (100 g) was added and the mixture was partitioned between dichloromethane and carbonate and 10% aqueous sodium. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 ml). The combined dichloromethane extracts were dried (CMgSO ₄ ) and concentrated in vacuo to give an oil that was purified by column chromatography on silica eluting with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colorless oil.

Yield: 10.5 g.

R.M.N.-H CCDCl ..,) δ = 7.30-7.00 Cm, 3H); 3.60 Cm, 2H);

3.20 Cm, 2H); 3.00-2.85 Cm, 4H); 2.20-2.05 Cm, 2H) ppm.

Re i v i nài c aces there. Process for the preparation of a compound of formula <I) ’

or a pharmaceutically acceptable salt thereof, where m is 1 or 2!

R ^ 'and R', each independently, represent H or in which alkyl C. _s -C ^ or represent »together where p is an integer from 2 to 5j

R ~ represents H or C 1 -C ₄ alkyl;

Λ 4 · represents a direct link, -CH ...-, ~ CH ._, O- or

-CH .-. S-;

R represents a group of structure formula, ’• (CH.) · P

Where

(CH) çr Het / ² q .¼ f “«

R and R each represent C -C ^, a1c oxy-C $ -C ^, romethyl, cyano, -i.CH.NR 2 n

-0C0 <here n i ndependent ternente —t. L-H ...) OH, ha 1 o, n

R, ~ C0 <alkyl

CH (OH) (a1qu i1

H, altri fluoro ^C 1 ^_C '4'',

W 'í ’4‘ * ·.

- <CH._,) CONR ^Z R ^y 2 ri ~ C (OH> C to 1qu i1 Cj “C ^>,

- <CH -) COOChere 1 C.-C.);

, ₇ 4 g í 4

R 'and R' '' each independently represent H or a3. Here 1st C., -C ^ n is 0, 3. or 2;

X and X each represent independently U or CH ...,;

q is 1, 2 or 3;

Het represents pyridyl, pyrazinyl or thienyl, or characterized by compendends (in addition to the reaction of a compound of formula

2. m • NHR '(II) where R ", R', R 'and m are defined in the same way as before, with a compound of formula!

Q-CH .-, - 2-R where 2 and R ^ are defined in the same way as before and Q is a leaving group, what? ' (b) cyclisation of a compound of formula;

(111)

Ph

NC CN

R ¹ R ³ with a concentrated mineral acid *, where R ^ ', R', R '', and R **, m ε 2 are defined in the same way as above, with * those processes Ca) or Cb) being followed optionally by converting * the * product of formula (structure C1) to a pharmaceutically acceptable salt.

2nd. Process * according to claim 1, characterized in that in part Ca), Q is Cl, Br, 1 or methanesulfonyloxy and the reaction * is carried out in the presence of an acid acceptor * and, in part Cb), the acid * concentrated mineral being acid * hydrochloric * concentrated *.

Sure. Characterized * Process of because m is 2, B.C 1 H R “'be methyl * , & be CH.-, © R

, 4 ture í

Claims (1)

the claim is a group * of structural formula R or X ί jfc ί * q q where R 'and R' ~ are each independently chosen from H, halo, hydroxy and C, alkyl, C4 and X and X are defined as in claim .1. . 45 ~ enter even i— i sbua, December 10, yy30